An Atypical Cutaneous Metastasis in a Case of Clear Cell Renal Carcinoma

Clear cell renal cell carcinoma (ccRCC) comprises most renal cell carcinoma (RCC) cases, with its incidence increasing in recent years. Metastases are most commonly found in the lungs, bones, liver, and brain. However, few patients present with cutaneous metastases, which are usually associated with poor outcomes. We present the case of a 52-year-old man with ccRCC and skin metastasis. Our aim was to highlight the variability in the presentation of cutaneous metastasis of ccRCC. Clinicians should be aware of the various manifestations and possible locations of RCC skin metastases to better identify these lesions and further guide treatment.


Introduction
Kidney cancer is the ninth most common malignancy in the United States [1]. Clear cell renal cell carcinoma (ccRCC) comprises 75% of these cases, with incidence increasing in recent years. It accounts for approximately 2% of cancer diagnoses and deaths worldwide. Developing countries, like Colombia, have fewer incidence rates, with less information on poor-income areas [2].
Metastases are most frequently seen in the lungs, bones, liver, and brain [1]. Hematogenous spread may result in an unusual metastatic pattern such as muscular or cutaneous disease [1]. As many as 3% of patients present with cutaneous metastases, which usually are associated with a poor outcome [3,4]. Skin metastases of internal tumors, including kidney cancer, have also increased in the last decade [4].
Frequent clinical manifestations of cutaneous metastasis include painless red nodules and plaques [4]. Ulcers, and pink papules, among several other presentations, including inflammatory, cicatricial, and bullous lesions, have been reported but are not as frequent [4,5]. Blue-colored presenting lesions have been described as a unique presentation of renal cancer, liver cancer, and neuroblastomas [4].
When a metastatic skin lesion is suspected, a thorough work-up including a skin biopsy with appropriate histologic stains should be performed [4]. A biopsy can also be used to establish the primary malignancy if unknown, as the histopathologic appearance of the metastatic tissue may mimic the primary tumor [5].
We found other case reports of cutaneous involvement of renal cell carcinoma (RCC). In most of these reports, the presenting lesion consisted of a nodule or a pedunculated lesion, which is the classical presentation of skin metastases of RCC [1,3,[6][7][8][9][10].
We present the case of a 52-year-old man with an atypical presentation of cutaneous metastasis of ccRCC and highlight the importance of considering the variability of clinical manifestations and locations of ccRCC cutaneous metastases.

Case Presentation
We present the case of a 52-year-old African American male with a past medical history of ccRCC of the right kidney, ISUP grade 4, TNM stage IV: T2N0M1, with metastases to lung and bone, who had undergone radical nephrectomy of the right kidney and five cycles of treatment with pembrolizumab and axitinib. He presented to the dermatology service with a four-month-old lesion on the scalp associated with bleeding and headache. On physical examination, a 3-cm pedunculated, ulcerated mass with bleeding stigmata was noted in the coronal region of the scalp ( Figure 1A). Computed tomography (CT) of the skull was ordered ( Figures 1B, 1C), which revealed an exophytic mass on the scalp of the right parietal region, highly vascularized, measuring 20 x 30 x 30 mm, with deep subgaleal involvement, without periosteal infiltration or intracranial involvement. With these results, resection of the scalp tumor with coverage using a diadem flap was planned and performed by plastic surgery. The histopathological study revealed a tumorous lesion that occupied the dermis and subcutaneous cellular tissue, with extensive ulcerated areas, foci of necrosis, and hemorrhage ( Figure 2A). The specimen was composed of rows, sheets, and tubular structures containing cells with abundant clear and eosinophilic cytoplasm, vesicular chromatin nuclei, prominent nucleolus, and frequent mitotic figures (up to 4 per highpower field). There were foci of lympho-histio-plasmacytic infiltrate. The resection margins were free of tumor involvement. Regarding the immunohistochemical study, a cocktail of CK+, CD10+, PAX 8+, RCC marker+, CAIX-, CD34-, CK7-, and CK20-was obtained ( Figures 2B-2E). With these findings, the diagnosis of skin involvement of ccRCC was made.
Six months later, during follow-up, a new CT showed no new metastases and the patient continued outpatient oncology care.

Discussion
Cutaneous metastases are not a common finding in the setting of ccRCC [1][2][3][4][5][6][7]. They are usually seen in the final stages of the disease but can be found at any stage and at any time [7]. Our patient's time of presentation is consistent with the timing described in the literature, as he had a stage IV ccRCC.
Some typical sites of cutaneous metastases are the chest and the abdomen due to anatomic proximity to the kidneys, and the scalp due to lymphohematogenous dissemination, as noted above [7]. Our case shows these features; however, its presentation is unique in the sense that the characteristics of the lesion are atypical. The painful, ulcerated nature of the lesion and the hemorrhage are not consistent with the most common descriptions of metastatic ccRCC skin lesions in other reports we found [1,3,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The findings of such reports are comprised in Table 1.  It is clear that the lesion in our case was easily identified because of the pain, size, and location. However, the typical lesion is painless and small, and does not bleed, which makes it easily overlooked by patients and healthcare providers. This raises concern because the asymptomatic nature of presenting lesions may delay identification or treatment of the condition.

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Another characteristic that stands out in our case report is the high vascularity found in the CT scan and the bleeding stigmata present during the physical examination, which is paradoxical considering that the patient had undergone five cycles of antiangiogenic therapy with axitinib at the time of presentation. This calls into question the efficacy of the said treatment for cutaneous metastasis of ccRCC given that the patient's internal metastasis did respond to adjuvant treatment.
Our patient was a surgical candidate and underwent resection of the mass with success, exhibiting no recurrence at six months. This finding reinforces the role of surgical treatment as the gold standard for these lesions. Dismissal of the initial lesion for its unusual characteristics would have been unfortunate considering its complete resolution with treatment. Clinicians should be encouraged to have a low threshold of suspicion when it comes to the inspection of the skin of patients with ccRCC, as cutaneous metastases are heterogeneous in nature and can be easily mistaken for benign conditions [4].

Conclusions
Cutaneous metastases of ccRCC are infrequent manifestations of the primary tumor. Patients can present with a variety of skin lesions ranging from more commonly encountered ones, such as nodules and plaques, to rare ones, such as ulcerated exophytic lesions. It is crucial that general practitioners, oncologists, and dermatologists perform detailed skin examinations in patients with internal tumors, especially ccRCC. This ensures that possible skin metastases are identified timely and get proper treatment. The metastatic lesion may even be the initial presentation of the internal tumor. Failure to identify these lesions can result in irresectable masses that further increase morbidity and mortality.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.